Reversal of neurosteroid effects at α4β2δ GABAA receptors triggers anxiety at puberty

Abstract

Puberty is characterized by mood swings and anxiety, often produced by stress. Here, we show that THP (allopregnanolone), a steroid released by stress, increases anxiety in pubertal female mice, a reversal of its well-known anxiety-reducing effect in adults. Anxiety is regulated by GABAergic inhibition in limbic circuits. Although this inhibition is increased by THP before puberty and in adults, THP reduced tonic inhibition of CA1 hippocampal pyramidal cells at puberty, leading to increased excitability. This paradoxical effect of THP was due to inhibition of α4βδ GABA A receptors. These receptors are normally expressed at very low levels, but at puberty, their expression was increased in CA1 hippocampus where they generated outward currents. THP also decreased outward current at recombinant α4β2δ receptors, an effect dependent on arginine 353 in the α4 subunit, a putative Cl − modulatory site. Thus, inhibition of α4β2δ GABA A receptors by THP provides a mechanism for anxiety at puberty.The onset of puberty is associated with increases in emotional reactivity and anxiety 1,2 . Responses to stressful events are amplified 3 , and anxiety and panic disorder first emerge at this time 2 , twice as likely to occur in girls than in boys 2 . Few studies have addressed the biological basis of this important issue, although suicide risk increases in adolescence, despite the use of adult-based medical strategies 2 .The GABA A receptor plays a pivotal role in the generation of anxiety 4 . This receptor is the target for endogenous steroids such as THP (3α-OH-5α [β]-pregnan-20-one or [allo] pregnanolone), which increase GABA-gated currents at physiological concentrations 5 of the steroid. THP is a metabolite of the ovarian/adrenal steroid progesterone, but is also formed in the brain as a compensatory response to stress 6 . In adults, THP potently reduces anxiety in humans 7 , an effect seen in animal models with direct administration into the dorsal CA1 hippocampus 8 , part of the limbic system that regulates emotion. It is generally accepted that * Correspondence and requests for materials should be addressed to S.S.Smith, Dept. of Physiology and Pharmacology, SUNY Downstate Medical Center, 450 Clarkson Ave., Brooklyn, NY 11203 USA; phone: 718-270-2226; FAX: 718-270-3103; email: Sheryl.smith@downstate NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript the GABA-enhancing action of THP underlies its well-known anxiety-reducing effect in adults, which is similar to other GABA-enhancing drugs such as the benzodiazepines.GABA A receptors are pentamers formed predominantly of 2α, 2β and 1γ subunits 9 which gate a Cl − current and produce most fast synaptic inhibition in the brain. Substitution of the δ subunit for γ2 yields a receptor with the highest sensitivity to steroids such as THP 10-12 . These highly sensitive δ-GABA A receptors are extrasynaptic 13 , and mediate tonic rather than synaptic inhibition in areas such as dentate gyrus 14 . Thus, THP and related steroids enhance inhibition h...

5α-Reductase Inhibition Prevents the Luteal Phase Increase in Plasma Allopregnanolone Levels and Mitigates Symptoms in Women with Premenstrual Dysphoric Disorder

“…However the same effects on behavior were not present in asymptomatic controls with no past history of PMDD who underwent the identical protocol. These data suggest that women with PMDD have a differential sensitivity to changes in allopregnanolone levels, perhaps at the level of the GABA A R (Backström et al, 2011) (possibly reflecting an increased expression of the α4βδ GABA-A receptor in PMDD that could result in allopregnanolonemediated decreased inhibition and anxiety-like behaviors (Shen et al, 2007)), or secondary to an altered metabolism of allopregnanolone and other neurosteroids within the CNS. The role of progesterone and its 5α-reduced metabolites in affective regulation is supported by several findings in humans (Schiller et al, 2014).…”

“…Allopregnanolone regulates central GABA-A receptor function and hence CNS excitation (Majewska et al, 1986;Paul and Purdy, 1992;Maguire et al, 2005;Shen et al, 2007). In one study, higher plasma levels of allopregnanolone was associated with less severe PMDD symptoms (Wang et al, 1996); however, abnormal plasma allopregnanolone levels have not been consistently observed in PMDD (Schmidt et al, 1994;Wang et al, 1996;Rapkin et al, 1997;Monteleone et al, 2000;Epperson et al, 2002;Lombardi et al, 2004;Schiller et al, 2014).…”

Progesterone selectively increases amygdala reactivity in women

“…58 Specifically, allopregnanolone inhibits the a4b2d GABA A receptor, which reduces tonic inhibition and thereby increases excitability. Because this receptor is highly sensitive to neurosteroids, inhibition of this receptor at relatively low neurosteroid concentrations can induce paradoxical effects, 59 and may contribute to amygdala disinhibition.…”

An association of early puberty with disordered eating and anxiety in a population of undergraduate women and men

“…For example, neuron number in the prefrontal cortex differs in adolescent and adult rats (Markam et al, 2007), and neurons of the medial amygdala differ in structure among pre-, mid-, and late adolescent male hamsters (Zehr et al, 2006). Furthermore, adolescent rodents show differential responsiveness to anxiogenic situations, which is directly related to different effects of neurosteroids on cell excitability in adolescents and adults (Shen et al, 2007). In humans, there are dramatic adolescent decreases in the percentage of gray matter in frontal and temporal lobes (reviewed in Lenroot & Giedd, 2006), brain regions which are linked with disordered eating behavior (Uher & Treasure 2005) and anxiety (Garakani et al, 2006).…”